We have cloned the cDNA for human apolipoprotein (apo)B-100, the ligand on low density lipoproteins which interacts with the LDL receptor and initiates receptor mediated endocytosis and LDL catabolism. The normal human liver apoB-100 mRNA is 14 kb long encoding a mature apoB-100 protein of 4536 amino acids with a molecular weight of 512,723 daltons. The delineation of the entire human apoB-100 sequence will now permit a detail analysis of the conformation of the protein, the LDL receptor binding domain(s), the structural relationship between apoB-100 and apoB-48, and may provide the basis for the study of the genetic defects of the dyslipoproteinemias. We have also evaluated the expression of apoB mRNA in the liver and intestine by Northern blot. Human liver synthesize a single 14 kb mRNA of apoB-100, however, the intestine contained both the apoB-100 mRNA and a 7.5 kb mRNA which encode apoB-48. Result of further blot hybridization analysis with specific synthetic oligonucleotide probes showed apoB-48 mRNA contain the 5' end but not the 3' end of apoB-100 mRNA. The novel finding that human intestine synthesize both the apoB-100 and apoB-48 mRNA will now require the restructuring of the currently held concepts of human lipoprotein synthesis in normal subjects and in patients with dyslipoproteinemias. Studies on the structural organization of the apoB gene and its expression in patients with no plasma apoB (abetalipoproteinemia) have also been initiated. Southern blot hybridization showed no major rearrangement or deletion in the apoB gene of these patients. Northern blot and dot blot hybridization studies revealed apoB-100 mRNA are being produced by the liver cells of these patients at an elevated level than in normal subjects. Our data support the concept of a post-translational defect in apoB processing or secretion which leads to defective secretion of cellular lipoproteins and a virtual absence of apoB containing plasma lipoproteins in these subjects.